Brominated Flame Retardants Pollution and Health Risk---Effects of Decabrominated Diphenyl Ether (Deca-BDE) on Reproductive, Hepatic, and Endocrine Functions in Mice

[[abstract]]十溴聯苯醚(Decabrominated diphenyl ether, Deca-BDE) 為多溴聯苯醚(polybrominated diphenylethers, PBDEs)209種同類異構物中被廣泛使用之溴系阻燃劑(Brominated flame retardants, BFRs)，PBDEs化學結構類似甲狀腺荷爾蒙及多氯聯苯(polychlorinated biphenyls, PCBs)。BFRs在1970年代開始添加於各類產品中，目的是阻止聚合物材料引燃，或抑制火燄 蔓延。最近幾年的研究報告指出，PBDEs已成為新的環境污染物，除了陸地動物、海洋生物， 各國婦女母乳中PBDEs的含量亦日益升高，而目前對Deca-BDE相關的生殖、肝臟與荷爾蒙 的研究仍有限。今年本研究團隊首度發表直接暴露於Deca-BDE可能透過氧化傷害影響雄性 小鼠之生殖功能，並發現最低觀察危害效應劑量(lowest-observed-adverse-effect level, LOAEL) 為500 mg/kg。然而此暴露是否同時引發甲狀腺荷爾蒙或肝臟酵素的影響？Deca-BDE是否會 通過胎盤而對子代造成危害？雄性子代(F1)的生殖危害是否會傳輸至雄性第二子代(F2)？均 引起我們研究的興趣而有待進一步探討。三年期研究計畫目標包括：一、探討直接暴露 Deca-BDE是否影響甲狀腺荷爾蒙調控或肝臟酵素活性；二、評估胎兒在子宮內暴露不同濃 度的Deca-BDE，是否影響雄性F1成長後的生殖功能、甲狀腺荷爾蒙調控或肝臟酵素活性； 三、雄性F1的生殖危害是否會傳輸至雄性F2，若有影響是否與F1及F2生殖細胞的DNA甲基化 改變有關。實驗方法將建立CD-1小鼠的動物模式，藉由離乳小鼠直接暴露Deca-BDE與子宮 內至泌乳時期之暴露與交錯繁殖設計，以肝臟酵素活性、血清甲狀腺荷爾蒙濃度、精子功能、 精子反應性氧化物質產生、睪丸造精過程DNA含量、組織學、凋亡相關基因與造精過程相關 基因BC009436表現、精子染色質DNA結構、精子整體DNA甲基化程度、甲基化敏感限制酶 與聚合酶鏈反應等分析方法，探討Deca-BDE如何改變生殖細胞，以及如何將此危害傳輸至 子代的影響。相信此研究結果在環境與工業衛生的領域，將使我們更清楚瞭解Deca-BDE的 作用機制，並有助於評估BFRs污染對人類及與生態之健康風險。[[abstract]]Polybrominated diphenyl ethers (PBDEs) are widely used as additive brominated flame retardants (BFRs) and chemically similar to dioxins and polychlorinated biphenyls (PCBs). Among 209 congeners of PBDEs, decabrominated diphenyl ether (Deca-BDE) is the most used BFRs in constructed materials. The first BFRs were taken off the market in the early 1970s. Nowadays, PBDEs have been found in dust, vegetables, aquatic mammals, territorial mammals and to have increased in human milk. Little is known about the adverse health effects of PBDEs on reproductive, hepatic, and hormone systems. We have investigated that neonatal exposure to Deca-BDE can alter sperm function via oxidative stress in sexually mature rats in adulthood and the lowest-observed-adverse-effect level (LOAEL) for sperm function to be 500 mg/kg in male mice. However, whether neonatal exposure of Deca-BDE causes developmental toxicity, thyroid hormone disruption, and hepatic enzymes induction and whether transgenerational effects occur from male offspring F1 to F2 are to our interesting and needed warrant further investigations. The specific objectives of this 3-year project are to evaluate (a) the effects of neonatal exposure to Deca-BDE on thyroid hormone homeostasis and hepatic enzymes induction in male mice, (b) the effects of developmental exposure to Deca-BDE on male reproductive function, thyroid hormone homeostasis and hepatic enzymes induction in F1 generation, and (c) the effects on reproduction correlate with altered DNA methylation in the germ line to multiple generations? An outcross experiment will be performed to determine whether the transgenerational phenotype is tranfmitted through the male germ line. The measurements of epididymal sperm count, motility, velocity, reactive oxygen species (ROS) generation, testicular DNA content in spermatogenesis, histopathology, apoptosis-related and BC009436 gene expression, sperm chromatin DNA structure, global sperm DNA methylation as well as methylation-sensitive restriction enzyme digestion analysis using a polymerase chain reaction (PCR) will be assessed to determine changes between controls and Deca-BDE-exposed mice. These results may one day be used in the development of means of assessing human and ecological risk associated its production, use and disposal for environmental and occupational health.[[note]]NSC96-2314-B327-001-MY